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Amidate-based ligands ( N -( tert -butyl)isobutyramide, ITA ) bind κ 2 to form homoleptic, 8-coordinate complexes with tetravalent 237 Np (Np(ITA) 4 , 1-Np ) and 242 Pu (Pu(ITA) 4 , 1-Pu ). These compounds complete an isostructural series from Th, U-Pu and allow for the direct comparison between many of the early actinides with stable tetravalent oxidation states by nuclear magnetic resonance (NMR) spectroscopy and single crystal X-ray diffraction (SCXRD). The molecular precursors are subjected to controlled thermolysis under mild conditions with the exclusion of exogenous air and moisture, facilitating the removal of the volatile organic ligands and ligand byproducts. The preformed metal-oxygen bond in the precursor, as well as the metal oxidation state, are maintained through the decomposition, forming fully stoichiometric, oxidation-state pure NpO 2 and PuO 2 . Powder X-ray diffraction (PXRD), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) elemental mapping supported the evaluation of these high-purity materials. This chemistry is applicable to a wide range of metals, including actinides, with accessible tetravalent oxidation states, and provides a consistent route to analytical standards of importance to the field of nuclear nonproliferation, forensics, and fundamental studies.

Traditional models of lanthanide electronic structure suggest that bonding is predominantly ionic, and that covalent orbital mixing is not an important factor in determining magnetic properties. Here, 4f orbital mixing and its impact on the magnetic susceptibility of Cp' 3 Eu (Cp' = C 5 H 4 SiMe 3 ) was analyzed experimentally using magnetometry and X-ray absorption spectroscopy (XAS) methods at the C K-, Eu M 5,4 -, and L 3 -edges. Pre-edge features in the experimental and TDDFT-calculated C K-edge XAS spectra provided unequivocal evidence of C 2p and Eu 4f orbital mixing in the π-antibonding orbital of a' symmetry. The charge-transfer configurations resulting from 4f orbital mixing were identified spectroscopically by using Eu M 5,4 -edge and L 3 -edge XAS. Modeling of variable-temperature magnetic susceptibility data showed excellent agreement with the XAS results and indicated that increased magnetic susceptibility of Cp' 3 Eu is due to removal of the degeneracy of the 7 F 1 excited state due to mixing between the ligand and Eu 4f orbitals., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Study Design: This is an experiential article based on the past 6 years experience of providing facial gender confirmation surgery (fGAS) at an academic medical center., Objective: While trainees are getting increasing exposure to aspects of facial gender affirming surgery (fGAS), the gap between trained providers and patients who can access care is currently still widening. A handful of fellowships across the country have emerged that include fGAS in their curriculum, but it will take another decade before the principles of affirming care and surgeries are systematically taught. Fortunately, the surgical principles and techniques required to perform fGAS are part of the skill set of any specialty surgeon trained in adult craniofacial trauma and esthetic facial surgery/rhinoplasty. It is the aim of this article to provide directly applicable knowledge with the goal to assist surgeons who consider offering fGAS in flattening the learning curve and hopefully contribute to increasing the quality of care provided for the transgender and gender diverse population. We hope to provide the reader with a very tangible article with the aims to 1) provide a simple systematic framework for an affirming consultation and preoperative assessment and 2) provide translatable surgical pearls and pitfalls for forehead feminization and gonial angle resection. The frontal sinus set back and gonial angle resection in our opinion are the most unique aspect to fGAS as rhinoplasty, genioplasty and other associated procedures (e.g., fat grafting) follow well established principles. We hope that the value of this article lies in the translatability of the presented principle to any practice setting without the need for VSP, special surgical instruments or technology beyond basic craniofacial tools., Methods: This is an experiential article based on the senior authors 6 year experience offering fGAS in an academic setting. The article is structured to outline both pearls and pittfalls and is supplemented by photographs and a surgical video., Results: A total of 19 pearls and pitfalls are outlined in the article., Conclusions: Facial gender affirming surgery mostly follows established craniofacial and esthetic surgery principles. Forehead feminization and gonial angle feminization are the 2 components that diverge most from established surgical techniques and this article hopefully provides guidance to shorten the learning curve of surgeons., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Lipomas are a rare cause of posterior interosseous nerve (PIN) compression. A systematic review of predictors for motor recovery has not been performed. This study sought to evaluate whether patient or lipoma characteristics are associated with motor recovery and could be used to determine when immediate tendon transfers at the time of excision should be performed., Methods: Articles describing patients with forearm lipomas resulting in PIN compression with motor weakness were included. Patient age, gender, symptom duration, laterality and largest dimension of lipoma, surgical intervention, and motor recovery were identified. Article quality was assessed via the Methodological Index for Non-Randomized Studies criteria., Results: Thirty articles reporting on 34 patients were identified. Average age was 58.2 years. Average largest lipoma dimension was 5.7 cm. All patients underwent lipoma removal, and 2 had concomitant tendon transfers. In all, 73.5% of patients had complete motor recovery at an average of 9.7 months. Patient age and largest dimension of lipoma, and duration of symptoms were not significant predictors of motor recovery. Symptom duration was a significant predictor of motor recovery in binary regression, particularly if < 18 months., Conclusions: The majority of patients with PIN weakness secondary to lipoma are likely to have complete motor recovery after excision alone. Concomitant tendon transfers should be considered for patients symptomatic for greater than 18 months. Further, adequately powered, studies are required to stratify risk factors and evaluate other modalities to identify the minority of patients who would benefit from immediate tendon transfer., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KC is a consultant for Checkpoint Surgical. Cleveland, OH. CC, AP, SG declare that they have no conflict of interest.

Synthesis of a series of hydrocarbon-soluble triarylamines bearing F, CF 3 , and Br substituents showing quasi-reversible redox events in the 0.59-1.32 V range is reported. Chemical oxidation of the amines was carried out with 0.5PhI(OAc) 2 /Me 3 SiX/Na[RCB 11 Cl 11 ] (X = Cl or OTf, R = H or Me), and a few aminium salts were isolated as pure solids.

Background: The pathophysiology of vasospasm (VS) after non-traumatic subarachnoid hemorrhage is not completely understood. Several risk factors associated with VS were previously reported, partially with conflicting results. The aim of this study was to identify patients at increased risk for VS., Methods: Retrospective analysis of data from all patients treated in our institutional intensive care unit (ICU) between 2010 and 2016 after non-traumatic subarachnoid hemorrhage. Possible contributing factors for VS studied were: age, sex, aneurysm-localization, treatment option, ICU-stay, ICU mortality, pre-existing condition, medication history, World Federation of Neurosurgical Societies (WFNS) grading system, modified Fisher scale., Results: We obtained data from 456 patients. 184 were male and 272 female patients, respectively. Mean age was 57.7±13.9 and was not different between sexes. In 119 patients, VS was diagnosed after subarachnoid hemorrhage. Incidence of VS was not different between sexes (male: 22.3%, female: 28.7%, P=0.127). Patients with VS were significantly younger (mean age 52.2 vs. 59.7, P<0.001), meanwhile patients aged 36-40 yrs. had the highest incidence of VS. Most VS were found after rupture of middle cerebral artery-aneurysms. Higher incidence of VS was found after aneurysm clipping compared to coiling. VS developed more often in patients with more severe WFNS grade and Fisher scale. In multivariate analysis, age, previous drug abuse and history of anticoagulants were associated with the incidence of VS., Conclusions: Younger age, middle cerebral artery-aneurysms, aneurysm clipping, previous drug abuse and history of anticoagulants were associated with a higher incidence of VS after non-traumatic subarachnoid hemorrhage. No gender difference was found.

Background: There is limited epidemiological evidence on Lassa fever in pregnant women with acute gaps on prevalence, infection incidence, and risk factors. Such evidence would facilitate the design of therapeutic and vaccine trials and the design of control programs. Our study sought to address some of these gaps by estimating the seroprevalence and seroconversion risk of Lassa fever in pregnant women., Methodology/principal Findings: We conducted a prospective hospital-based cohort between February and December 2019 in Edo State, Southern Nigeria, enrolling pregnant women at antenatal clinic and following them up at delivery. Samples were evaluated for IgG antibodies against Lassa virus. The study demonstrates a seroprevalence of Lassa IgG antibodies of 49.6% and a seroconversion risk of 20.8%. Seropositivity was strongly correlated with rodent exposure around homes with an attributable risk proportion of 35%. Seroreversion was also seen with a seroreversion risk of 13.4%., Conclusions/significance: Our study suggests that 50% of pregnant women were at risk of Lassa infection and that 35.0% of infections might be preventable by avoiding rodent exposure and conditions which facilitate infestation and the risk of human-rodent contact. While the evidence on rodent exposure is subjective and further studies are needed to provide a better understanding of the avenues of human-rodent interaction; public health measures to decrease the risk of rodent infestation and the risk of spill over events may be beneficial. With an estimated seroconversion risk of 20.8%, our study suggests an appreciable risk of contracting Lassa fever during pregnancy and while most of these seroconversions may not be new infections, given the high risk of adverse outcomes in pregnancy, it supports the need for preventative and therapeutic options against Lassa fever in pregnancy. The occurrence of seroreversion in our study suggests that the prevalence obtained in this, and other cohorts may be an underestimate of the actual proportion of women of childbearing age who present at pregnancy with prior LASV exposure. Additionally, the occurrence of both seroconversion and seroreversion in this cohort suggests that these parameters would need to be considered for the development of Lassa vaccine efficacy, effectiveness, and utility models., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kayem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Evidence from previous studies suggest that Lassa fever, a viral haemorrhagic fever endemic to West Africa has high case fatalities, particularly in pregnancy. While there have been remarkable innovations in vaccine development, with some Lassa vaccines undergoing early clinical trials. An understanding of Lassa antibody kinetics and immune responses will support vaccine design and development. However, there is currently no evidence on the antibody kinetics of Lassa (LASV) in pregnancy. Our study sought to estimate the efficiency of transplacental transfer of LASV IgG antibodies from the mother to the child., Methodology/principal Findings: The study made use of data from a prospective hospital-based cohort of pregnant women enrolled at the antenatal clinic and followed up at delivery between February and December 2019. Blood samples from mother-child pairs were evaluated for antibodies against Lassa virus. The study demonstrates a transplacental transfer of LASV IgG of 75.3% [60.0-94.0%], with a significant positive correlation between maternal and cord concentrations and a good level of agreement. The study also suggests that transfer may be more variable in women with 'de novo' antibodies compared to those with pre-existing antibodies., Conclusions/significance: The study shows that maternal antibody levels play an important role in determining transfer efficiency of Lassa antibodies to the new-born; and while the evidence is preliminary, the study also suggests that transfer efficiency may be less stable in acute or recent infection, as such timing of vaccination before pregnancy, that is in women of childbearing age may be more appropriate for protection of both pregnant women and their neonates., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kayem et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pressure injuries are a frequent complication in intensive care unit (ICU) patients, especially in those with comorbid conditions such as chronic obstructive pulmonary disease (COPD). Yet no epidemiological data on pressure injuries in critically ill COPD patients are available., Objective: To assess the prevalence of ICU-acquired pressure injuries in critically ill COPD patients and to investigate associations between COPD status, presence of ICU-acquired pressure injury, and mortality., Study Design and Methods: This is a secondary analysis of prospectively collected data from DecubICUs, a multinational one-day point-prevalence study of pressure injuries in adult ICU patients. We generated a propensity score summarizing risk for COPD and ICU-acquired pressure injury. The propensity score was used as matching criterion (1:1-ratio) to assess the proportion of ICU-acquired pressure injury attributable to COPD. The propensity score was then used in regression modeling assessing the association of COPD with risk of ICU-acquired pressure injury, and examining variables associated with mortality (Cox proportional-hazard regression)., Results: Of the 13,254 patients recruited to DecubICUs, 1663 (12.5%) had documented COPD. ICU-acquired pressure injury prevalence was higher in COPD patients: 22.1% (95% confidence interval [CI] 20.2 to 24.2) vs. 15.3% (95% CI 14.7 to 16.0). COPD was independently associated with developing ICU-acquired pressure injury (odds ratio 1.40, 95% CI 1.23 to 1.61); the proportion attributable to COPD was 6.4% (95% CI 5.2 to 7.6). Compared with non-COPD patients without pressure injury, mortality was no different among patients without COPD but with pressure injury (hazard ratio [HR] 1.07, 95% CI 0.97 to 1.17) or COPD patients without pressure injury (HR 1.13, 95% CI 1.00 to 1.27). Mortality was higher among COPD patients with pressure injury (HR 1.35, 95% CI 1.15 to 1.58)., Conclusion and Implications: Critically ill COPD patients have a statistically significant higher risk of pressure injury. Moreover, those that develop pressure injury are at higher risk of mortality. As such, pressure injury may serve as a surrogate for poor prognostic status to help clinicians identify patients at high risk of death. Also, delivery of interventions to prevent pressure injury are paramount in critically ill COPD patients. Further studies should determine if early intervention in critically ill COPD patients can modify development of pressure injury and improve prognosis., Competing Interests: Declaration of Competing Interest Stijn Blot received grants related to submitted work from the European Society of Intensive Care Medicine (ESICM) and the Flemish Society for Critical care Nurses (VVIZV) and outside the submitted work from Pfizer and 3 M. Ignacio Martin-Loeches received honoraria or grants outside the submitted work from MSD and Mundipharma. Louise Rose received honoraria or grants outside the submitted work from Draeger. All other authors: no competing financial interests, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Significantly fluorinated triarylmethyl cations have long attracted attention as potentially accessible highly reactive carbocations, but their isolation in a convenient form has proved elusive. We show that abstraction of chloride with a cationic silylium reagent leads to the facile formation of di-, tetra-, and hexafluorinated trityl cations, which could be isolated as analytically pure salts with the [HCB 11 Cl 11 ] - counterion and are compatible with (halo)arene solvents. The F 6 Tr + cation carrying six meta -F substituents was computationally predicted to possess up to 20% higher hydride affinity than the parent triphenylmethyl cation Tr + . We report that indeed F 6 Tr + displays reactivity unmatched by Tr + . F 6 Tr + at ambient temperature abstracts hydrides from the C-H bonds in tetraethylsilane, mesitylene, methylcyclohexane, and catalyzes Friedel-Crafts alkylation of arenes with ethylene, while Tr + does none of these., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Idiopathic pulmonary fibrosis (IPF) is a severe, progressive and irreversible lung disease constantly associated with a major vascular remodeling process. Endothelial colony-forming cells (ECFCs) are human vasculogenic cells proposed as a cell therapy product or liquid biopsy in vascular disorders. Since the link between IPF and thrombosis has been largely proposed, the aim of our study was to explore hypercoagulability states in ECFCs from patients with IPF. We performed Thrombin generation assay (TGA) in cord blood (CB)-ECFCs, peripheral blood (PB)-ECFCs and IPF-ECFCs. Endogenous thrombin potential and peak were higher in IPF-ECFCs compared to CB-ECFCs and PB-ECFCs. As thrombin generation in ECFCs was increased, we evaluated anticoagulant proteins expressed on ECFCs membrane and identified thrombomodulin and EPCR. We found a significant decrease of both anticoagulant proteins at membrane using flow cytometry. This study is the first to examine ECFC thrombin generation in IPF. This new finding strongly argues for a role of ECFC in IPF pathophysiology and thrombotic related disorders in IPF. Graphical Abstract.

Intermetallic porous SHS-TiNi alloys exhibit tangled and specific stress-strain characteristics. This article aims to evaluate the findings emanating from experiments using standard and proprietary instruments. Fatigue testing under repeated complex loading was used to measure the total number of load cycles before failure of the SHS-TiNi samples occurred. Of the tested samples, seventy percent passed through 10 6 cycles without failure due to the reversible martensite transformation in the TiNi phase, one of the prevailing constituents of a multiphase matrix. The fractured surfaces were analyzed using scanning electron microscopy and confocal laser scanning instruments. Microscopy studies showed that the entire surface of the sample is concealed by miscellaneous strata that result from the SHS processand effectively protect the porous alloy in a corrosive environment. Numerous non-metallic inclusions, which are also attributed to the SHS reaction, do not have a significant impact on the deformation behavior and fatigue performance. In this context, the successful in vivo functioning of porous grafts assessed in a canine rib-plasty model allows the bone substitute to be congruentially deformed in the body without rejection or degradation; it thus has a long operational life, often greater than 17 ×10 6 (22 × 60 × 24 × 540) cycles. It acknowledges the potential benefits of SHS-TiNi as a superior osteoplastic material and its high resistance to corrosion fatigue.

Background: During rhinoplasty, it is typically necessary to use cartilage to shape and support the final nasal construct to provide both form and function to the nose (Tanna et al. in Plast Reconstr Surg 141(1):137e-151e, 2018; Guyuron in Plast Reconstr Surg 105(6):2257-2259, 2000; Kim et al. in Ann Plast Surg 65(6):519-523, 2010). The septal cartilage is the ideal graft both for its ease of access and quality of cartilage. However, this graft is a limited resource, and economy of its use is important as to negate the need to harvest cartilage from the ear or rib., The Purpose: 1. To share the senior author's 40 years' experience with the economy of septal cartilage. 2. To identify the areas of the septal cartilage most suitable for a particular graft. 3. To discuss the common grafts that are used in rhinoplasty. 4. To identify when other sources of cartilage are needed and where to best use those grafts. 5. To present option for preservation of the leftover septal cartilage., Conclusion: Overall consideration should focus on the size, thickness, and curvature of the graft contemplating the structural and functional needs of the rhinoplasty maneuvers., Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients., Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis., Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9-27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6-16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2-1.8), stage II (OR 1.6; 95% CI 1.4-1.9), and stage III or worse (OR 2.8; 95% CI 2.3-3.3)., Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.

We report two outbreaks of Lassa fever that occurred in Benin in 2014 and 2016 with 20 confirmed cases and 50% (10/20) mortality. Benin was not previously considered to be an endemic country for Lassa fever, resulting in a delay to diagnose the disease and its human transmission. Molecular investigations showed the viral genomes to be similar to that of the Togo strain, which is genetically very different from other known strains and confirms the existence of a new lineage. Endemic circulation of Lassa virus in a new territory and the genetic diversity thus confirm that this virus represents a growing threat for West African people. Given the divergence of the Benin strain from the prototypic Josiah Sierra Leone strain frequently used to generate vaccine candidates, the efficacy of vaccine candidates should also be demonstrated with this strain.

Strain CS-1 T , a novel facultative anaerobic bacterium, was isolated from the larval gastrointestinal tract of the biting midge, Culicoides sonorensis , a vector of the epizootic haemorrhagic disease virus and the bluetongue virus. Cells were Gram-stain-positive, non-motile, non-spore-forming, pleomorphic rods. Optimal growth occurred at pH 7.5 and 37 °C. The G+C content of the genomic DNA was 38.3 mol%, estimated by using HPLC. The dominant cellular fatty acids were C 14 : 0 (45.9 %) and C 16 : 0 (26.6 %). The polar lipid profile comprised glycolipids, diphosphatidylglycerol, phospholipids and phosphoglycolipids. Respiratory quinones were not detected. Strain CS-1 T had very low 16S rRNA gene similarity to members of the phylum Firmicutes : Macrococcus canis KM45013 T (85 % similarity) and Turicibacter sanguinis MOL361 T (88 % similarity). Phylogenetic analysis based on 16S rRNA, rpoB, gyrB genes, and conserved protein sequences of the whole genome revealed that strain CS-1 T was related to members of the classes Bacilli and Erysipelotrichia within the phylum Firmicutes . Furthermore, average nucleotide identity and digital DNA-DNA hybridization analyses of the whole genome revealed very low sequence similarity to species of Bacilli and Erysipelotrichaceae ( Macrococcus canis KM45013 T and Turicibacter sp. H121). These results indicate that strain CS-1 T belongs to the phylum Firmicutes and represents a new species of a novel genus, family, order and class. Based on the phenotypic, chemotaxonomic, phylogenetic and genomic characteristics, we propose the novel taxon Culicoidibacter larvae gen. nov., sp. nov. with the type strain CS-1 T (=CCUG 71726 T =DSM 106607 T ) within the hereby new proposed novel family Culicoidibacteraceae fam. nov., new order Culicoidibacaterales ord. nov. and new class Culicoidibacteria classis nov. in the phylum Firmicutes .

The French Society of Intensive Care Medicine (SRLF), jointly with the French-Speaking Group of Paediatric Emergency Rooms and Intensive Care Units (GFRUP) and the French-Speaking Association of Paediatric Surgical Intensivists (ADARPEF), worked out guidelines for the management of central venous catheters (CVC), arterial catheters and dialysis catheters in intensive care unit. For adult patients: Using GRADE methodology, 36 recommendations for an improved catheter management were produced by the 22 experts. Recommendations regarding catheter-related infections' prevention included the preferential use of subclavian central vein (GRADE 1), a one-step skin disinfection(GRADE 1) using 2% chlorhexidine (CHG)-alcohol (GRADE 1), and the implementation of a quality of care improvement program. Antiseptic- or antibiotic-impregnated CVC should likely not be used (GRADE 2, for children and adults). Catheter dressings should likely not be changed before the 7th day, except when the dressing gets detached, soiled or impregnated with blood (GRADE 2- adults). CHG dressings should likely be used (GRADE 2+). For adults and children, ultrasound guidance should be used to reduce mechanical complications in case of internal jugular access (GRADE 1), subclavian access (Grade 2) and femoral venous, arterial radial and femoral access (Expert opinion). For children, an ultrasound-guided supraclavicular approach of the brachiocephalic vein was recommended to reduce the number of attempts for cannulation and mechanical complications. Based on scarce publications on diagnostic and therapeutic strategies and on their experience (expert opinion), the panel proposed definitions, and therapeutic strategies.

Porous TiNi alloys fabricated by self-propagating high-temperature synthesis (SHS) are biomaterials designed for medical application in substituting tissue lesions and they were clinically deployed more than 30 years ago. The SHS process, as a very fast and economically justified route of powder metallurgy, has distinctive features which impart special attributes to the resultant implant, facilitating its integration in terms of bio-mechanical/chemical compatibility. On the phenomenological level, the fact of high biocompatibility of porous SHS TiNi (PTN) material in vivo has been recognized and is not in dispute presently, but the rationale is somewhat disputable. The features of the SHS TiNi process led to a multifarious intermetallic Ti 4 Ni 2 (O,N,C)-based constituents in the amorphous-nanocrystalline superficial layer which entirely conceals the matrix and enhances the corrosion resistance of the unwrought alloy. In the current article, we briefly explore issues of the high biocompatibility level on which additional studies could be carried out, as well as recent progress and key fields of clinical application, yet allowing innovative solutions.

Importance: Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy., Objectives: To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides., Design, Setting, and Participants: This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population., Main Outcomes and Measures: Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response., Results: In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase., Conclusions and Relevance: This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission., Trial Registration: ClinicalTrials.gov identifier: NCT01686594.

Background: The intensive care unit (ICU) environment is prone to the risk of adverse events (AEs) and medication errors (MEs). The objective of this work was to describe a multidisciplinary safety program focused on AE and ME reporting and review in an ICU over a 7-year period., Methods: The program was implemented in an 18-bed medical ICU of a 2,200-bed university hospital. A multidisciplinary steering committee (intensivist, clinical pharmacist, nurses, and research assistants) met monthly. The first part of the meeting was dedicated to the review of events targeted through an internal voluntary reporting system, and the second part concerned the analysis of the previous month's events, according to a standardized method called Orion, inspired by the aeronautic industry., Results: A total of 808 AEs were reported, mostly related to medication processes (30.3% and 33.4% for prescription and administration, respectively). Among these, 526 AEs were related to medications (65.1%), of which 464 were MEs (88.2%). These MEs concerned mostly anti-infective drugs (23.5%) and related to wrong doses (35.8%). Among all AEs reported, 58 (43 MEs [74.1%]) were analyzed further and found to be associated with anti-infective (16.1%) and vasoactive drugs (16.1%). According to National Coordinating Council for Medication Error Reporting and Prevention classification, most AEs caused no harm to patients (category A-D: 38 events, 65.5%). Nurses were most often involved in the analysis (50.7%), along with pharmacists (37.5%). Training was identified as the most frequent corrective action (45.1%)., Conclusion: This program dedicated to AE and ME reporting, review, and analysis in ICU showed long-term engagement of the health care team in AE surveillance and helped in targeting measures for education, organization, and promoting teamwork and safety., Competing Interests: Disclosure SC reports personal fees from AstraZeneca and nonfinancial support from Boehringer Ingelheim, Actelion Pharmaceuticals, and MSD outside the submitted work. NT reports personal fees from Lilly Oncology, Boehringer Ingelheim, and Pfizer outside the submitted work. The other authors report no conflicts of interest in this work.

Background: Gender confirming primary breast augmentation is becoming more common. The purpose of this study was to compare the demographic and anatomical differences in cis-female and trans-female populations., Methods: This was a retrospective analysis of trans-female patients and cis-female patients undergoing primary breast augmentation at a single institution. Analysis included patient demographics and preoperative chest measurements including sternal notch to nipple distance (SSN), breast width (BW), nipple to inframammary fold distance (N-IMF), and nipple to midline distance (N-M). Continuous variables were compared using independent t tests, and discrete variables were compared using Pearson's χ 2 tests., Results: Eighty-two trans-female and 188 cis-female patients undergoing primary breast augmentation were included. Trans-female patients were older (40.37 versus 34.07), more likely to have psychological comorbidities (50% versus 12.23%), and had a higher body mass index, 27.46 kg/m 2 versus 22.88 kg/m 2 ( P = 1.91E-07), than cis-female patients. Cis-female patients most commonly had an ectomorph body habitus (52% versus 26%), whereas trans-female patients most commonly had an endomorph body habitus (40% versus 7%). Pseudoptosis or ptosis was more commonly seen in cis-female patients ( P = 0.0056). There were significant differences in preoperative breast measurements including sternal notch to nipple distance, BW, and N-M between groups, but not in N-IMF. The ratio of BW/N-IMF was statistically significant ( P = 2.65E-07 on right), indicating that the similarity in N-IMF distance did not adjust for the difference in BW., Conclusions: The trans-female and cis-female populations seeking primary breast augmentation have significant demographic and anatomical differences. This has implications for surgical decision-making and planning to optimize outcomes for trans-female patients.

Background: Proper evaluation and analysis of speech surgery outcomes for cleft-related velopharyngeal incompetence in children and young adults performed on humanitarian missions is poorly characterized. The aim of this study is to examine the effect of using a multidisciplinary team on cleft-related humanitarian missions. The effect on patient selection, velopharyngeal mechanism imaging, and speech outcomes after surgery will be highlighted., Methods: A review of the Medical Readiness Training Exercise database for craniofacial missions to the Dominican Republic from 2009 to 2011 was performed. A speech pathologist and a craniofacial surgeon evaluated all patients with a diagnosis of cleft palate and speech abnormalities. Patients were screened using speech analysis and selective nasal endoscopy. Data collected included sex, age, diagnosis, speech scores, date, and type of surgical procedure-that is, pharyngeal flap (PF) versus sphincter pharyngoplasty (SP), morbidity, and mortality., Results: One hundred twenty-six patients with cleft palate were screened during the study period by a craniofacial surgeon and secondarily by a speech pathologist. Twenty-eight patients were identified with nasal quality speech of whom 12 patients (12/126 = 9.5% of total surgical cases) underwent PF/SP surgery after previous primary repair of a cleft palate defect. The 16 remaining patients (16/28 = 57%) with nonsurgical speech abnormalities were determined that surgery was not going to be beneficial and they were spared unnecessary surgery after speech pathology evaluation and nasal endoscopy. Eight patients were female and 4 patients were male; average age was 13.3 years (range 4-27 years). Seven pharyngeal flaps (58%) and 5 (42%) sphincter pharyngoplasty procedures were performed. The average presurgical speech score was 11.4 (range 6-24). There was a significant decrease in postsurgical speech scores with the average postsurgical speech score of 5.2 (range 0-21, P value = 0.0028). Follow-up evaluation averaged 18 months (range 6-24). Average hospital stay was 2 days for PF/SP surgery. Two patients, both with developmental delay, retained speech scores greater than 6. There were no major complications or reoperations., Conclusions: Pharyngeal flap/sphincter pharyngoplasty surgery in young adults resulted in improved speech scores and comprehensibility after speech surgery on Medical Readiness Training Exercise military humanitarian missions. Speech surgery in older patients in relatively austere environments is safe and effective. After comprehensive multidisciplinary team evaluation, 43% of the patients who were screened to have velopharyngeal incompetence were identified as surgical candidates. Fifty-seven percent of patients evaluated by speech pathologist were recommend nonsurgical solution toward improving speech scores sparing them unnecessary surgery. The incorporation of a speech pathologist to the humanitarian mission resulted in identifying surgical candidates who would benefit the most from intervention and improved speech surgery outcomes.

Background: Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs)., Methods and Findings: A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 μg/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 μg/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present., Conclusions: Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.

Hypoxia mediates resistance to radio(chemo)therapy (RT) by stimulating the synthesis of hypoxia-related genes, such as osteopontin (OPN) and stress proteins, including the major stress-inducible heat shock protein 70 (Hsp70). Apart from its intracellular localization, Hsp70 is also present on the plasma membrane of viable tumor cells that actively release it in lipid vesicles with biophysical characteristics of exosomes. Exosomal Hsp70 contributes to radioresistance while Hsp70 derived from dying tumor cells can serve as a stimulator of immune cells. Given these opposing traits of extracellular Hsp70 and the unsatisfactory outcome of locally advanced lung tumors, we investigated the role of Hsp70 in the plasma of patients with advanced, non-metastasized non-small-cell lung cancer (NSCLC) before (T1) and 4-6 weeks after RT (T2) in relation to OPN as potential biomarkers for clinical response. Plasma levels of Hsp70 correlate with those of OPN at T1, and high OPN levels are significantly associated with a decreased overall survival (OS). Due to a therapy-induced reduction in viable tumor mass after RT Hsp70 plasma levels dropped significantly at T2 ( p  = 0.016). However, with respect to the immunostimulatory capacity of Hsp70 derived from dying tumor cells, patients with higher post-therapeutic Hsp70 levels showed a significantly better response to RT ( p  = 0.034) than those with lower levels at T2. In summary, high OPN plasma levels at T1 are indicative for poor OS, whereas elevated post-therapeutic Hsp70 plasma levels together with a drop of Hsp70 between T1 and T2, successfully predict favorable responses to RT. Monitoring the dynamics of Hsp70 in NSCLC patients before and after RT can provide additional predictive information for clinical outcome and therefore might allow a more rapid therapy adaptation.

Background: rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa., Methods: We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×10 7 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6-17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193., Findings: In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9-100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3-100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae., Interpretation: The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters., Funding: WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development)., (Copyright © 2017 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Bariatric surgery has emerged as an effective method of combating the morbid obesity epidemic. However, the massive weight loss that follows may result in contour changes that can affect body image and quality of life. Our study examines the effects and consequences of bariatric surgery and subsequent body contouring on body image and quality of life., Methods: Patients were prospectively followed up through their experience with bariatric surgery and subsequent body contouring surgery. Using 2 validated survey instruments, the Multidimensional Body-Self Relations Questionnaire and the Short Form 36 (SF-36), patients completed questionnaires preoperatively and at 6, 12, and 24 months postoperatively. Mean scores were determined by repeated measures analyses of variance F tests., Results: One hundred seventy-five patients were surveyed before bariatric surgery, with noted declines in survey completion at 6, 12, and 24 months. Appearance Evaluation scores improved significantly at all intervals (P = 0.0033), as did Body Area Satisfaction Scale and Appearance Orientation scores (P = 0.0079 and P = 0.044, respectively). While Overweight Preoccupation and Self-Classified Weight scores decreased over time, only the latter was significant (P < 0.0001). The composite SF-36 score for patients awaiting bariatric surgery (54.1%) with postoperative scores at 6 (67.6%,), 12 (at 74.0%), and 24 (76.7%) months being significantly higher (P < 0.0001). The body contouring group consisted of 41 patients who primarily had lower body procedures, with 31 patients surveyed at 6 months and 27 patients at 12 months. For this cohort, Appearance Evaluation and Body Area Satisfaction Scale scores both improved significantly (P = 0.0001 and P = 0.0005, respectively) whereas Appearance Orientation scores declined significantly (P = 0.0055). Both Overweight Preoccupation and Self-Classified Weight scores decreased with only the latter being statistically significant (P = 0.0286). Postoperative SF-36 scores at 6 (72.9%) and 12 (64.5%) months were no different than patients awaiting body contouring (71.3%)., Conclusions: Using 2 validated survey instruments, we show that patients undergoing bariatric surgery have improvements in body image and quality of life. Subsequent postbariatric body contouring surgery results in further improvements in body image. Our findings provide measurable evidence for the value of body contouring after significant weight loss, which may favor greater insurance coverage for this patient population.

A resting mean pulmonary artery pressure (mPAP) of 21-24 mmHg is above the upper limit of normal but does not reach criteria for the diagnosis of pulmonary hypertension (PH). We sought to determine whether an mPAP of 21-24 mmHg is associated with an increased risk of developing an abnormal pulmonary vascular response during exercise.Consecutive patients (n=290) with resting mPAP <25 mmHg who underwent invasive exercise haemodynamics were analysed. Risk factors for pulmonary vascular disease or left heart disease were present in 63.4% and 43.8% of subjects. An abnormal pulmonary vascular response (or exercise PH) was defined by mPAP >30 mmHg and total pulmonary vascular resistance >3 WU at maximal exercise.Exercise PH occurred in 74 (86.0%) out of 86 versus 96 (47.1%) out of 204 in the mPAP of 21-24 mmHg and mPAP <21 mmHg groups, respectively (OR 6.9, 95% CI: 3.6-13.6; p<0.0001). Patients with mPAP of 21-24 mmHg had lower 6-min walk distance (p=0.002) and higher New York Heart Association functional class status (p=0.03). Decreasing levels of mPAP were associated with a lower prevalence of exercise PH, which occurred in 60.3%, 38.7% and 7.7% of patients with mPAP of 17-20, 13-16 and <13 mmHg, respectively.In an at-risk population, a resting mPAP between 21-24 mmHg is closely associated with exercise PH together with worse functional capacity., (Copyright ©ERS 2016.)

The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10(-3) and 1.42 × 10(-3) mutations per site per year. This is equivalent to 16-27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15-60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.

Despite its importance for understanding human infertility and congenital diseases, early mammalian development has remained inaccessible to in toto imaging. We developed an inverted light-sheet microscope that enabled us to image mouse embryos from zygote to blastocyst, computationally track all cells and reconstruct a complete lineage tree of mouse pre-implantation development. We used this unique data set to show that the first cell fate specification occurs at the 16-cell stage.

Animal development is marked by the repeated reorganization of cells and cell populations, which ultimately determine form and shape of the growing organism. One of the central questions in developmental biology is to understand precisely how cells reorganize, as well as how and to what extent this reorganization is coordinated. While modern microscopes can record video data for every cell during animal development in 3D+t, analyzing these videos remains a major challenge: reconstruction of comprehensive cell tracks turned out to be very demanding especially with decreasing data quality and increasing cell densities. In this paper, we present an analysis pipeline for coordinated cellular motions in developing embryos based on the optical flow of a series of 3D images. We use numerical integration to reconstruct cellular long-term motions in the optical flow of the video, we take care of data validation, and we derive a LIC-based, dense flow visualization for the resulting pathlines. This approach allows us to handle low video quality such as noisy data or poorly separated cells, and it allows the biologists to get a comprehensive understanding of their data by capturing dynamic growth processes in stills. We validate our methods using three videos of growing fruit fly embryos.

Selective-plane illumination microscopy has proven to be a powerful imaging technique due to its unsurpassed acquisition speed and gentle optical sectioning. However, even in the case of multiview imaging techniques that illuminate and image the sample from multiple directions, light scattering inside tissues often severely impairs image contrast. Here we combine multiview light-sheet imaging with electronic confocal slit detection implemented on modern camera sensors. In addition to improved imaging quality, the electronic confocal slit detection doubles the acquisition speed in multiview setups with two opposing illumination directions allowing simultaneous dual-sided illumination. Confocal multiview light-sheet microscopy eliminates the need for specimen-specific data fusion algorithms, streamlines image post-processing, easing data handling and storage.

Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69(+)/CD94(+) NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC.

Background: A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa., Methods: For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193., Findings: Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing., Interpretation: The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy., Funding: WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development., (Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Since dialysis withdrawal in maintenance dialysis patients with limited life expectancy results always in short-term death, nephrologists need a referenced process to make their decision. This study reviews 8 years of operation of an Ethics Committee in Nephrology (ECN). The ECN, within a multidisciplinary team, once a month explores cases reported by caregivers when maintaining dialysis seems not to be in the patient's best interest. Discussion is required when the vital prognosis is engaged by the evolution of the chronic kidney disease (CKD) or the occurrence of an acute medical event. Data are analyzed using a discussion guide. The informed decision is completed with an appropriated palliative care project involving the patient, and recorded in their file. Since 2006, the ECN has deliberated yearly for 10 sessions on 6-18 cases, concerning 380 identified maintenance dialysis patients. Characteristics of the population, cases, sessions and proposals are recorded and analyzed. The only variable associated with dialysis withdrawal was having at least one new comorbid condition. End of life is supported with the help of the palliative care team in the hospital or exceptionally at home. The ECN, through a multidisciplinary deliberation and resolution process, proposes an ethical shared-decision-making model ensuring that dialysis withdrawal follows professional guidelines, and is registered as a method for evaluating professional practice (EPP). Annual activity reports are submitted to the Hospital's Medical Evaluation and Quality Unit. Benefits are individual and collective for patients, relatives and caregivers. Prospects for reducing non-implemented decisions and identifying cases earlier would improve the Committee effectiveness., (© 2015 The Authors. Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis.)

Mammalian development begins with the segregation of embryonic and extra-embryonic lineages in the blastocyst. Recent studies revealed cell-to-cell gene expression heterogeneity and dynamic cell rearrangements during mouse blastocyst formation. Thus, mechanistic understanding of lineage specification requires quantitative description of gene expression dynamics at a single-cell resolution in living embryos. However, only a few fluorescent gene expression reporter mice are available and quantitative live image analysis is limited so far. Here, we carried out a fluorescence gene-trap screen and established reporter mice expressing Venus specifically in the first lineages. Lineage tracking, quantitative gene expression and cell position analyses allowed us to build a comprehensive lineage map of mouse pre-implantation development. Our systematic analysis revealed that, contrary to the available models, the timing and mechanism of lineage specification may be distinct between the trophectoderm and the inner cell mass. While expression of our trophectoderm-specific lineage marker is upregulated in outside cells upon asymmetric divisions at 8- and 16-cell stages, the inside-specific upregulation of the inner-cell-mass marker only becomes evident at the 64-cell stage. This study thus provides a framework toward systems-level understanding of embryogenesis marked by high dynamicity and stochastic variability., (© 2015 The Authors.)

Background: Previous studies have examined national trends in breast reconstruction, using various data sets demonstrating increases in implant-based reconstruction and decreases in autologous reconstruction. However, academic breast reconstruction practices have never been specifically characterized. The University Health Consortium-Association of American Medical Colleges Faculty Practice Solutions Center database contains comprehensive, factual billing and coding data from 90 academic medical centers in the United States, and has been used to characterize practice patterns of various academic surgical specialties., Objective: To describe breast reconstruction trends unique to academic surgical practices, using the Faculty Practice Solutions Center database., Methods: Annual data for defined breast reconstruction procedures (current procedural terminology codes: 19340, 19342, 19357, 19361, 19364, 19366, 19367, 19369, and 19380) performed by university plastic surgeons during calendar years 2007 to 2013 were included in the study., Results: From 2007 to 2013, a 2-fold increase in the number of breast reconstruction procedures was observed (from a mean of 45.3 to 94.2 procedures per surgeon). During this period, implant-based reconstructions and autologous reconstructions rose in tandem (28.9-44.6 and 11.4-19.3, respectively), with a preserved 2.5:1 ratio between the 2 categories each year. When compared to reconstructions overall, the proportion of both implant reconstruction and autologous reconstruction procedures declined, since revision and other types of reconstructions increased (11% of all reconstructions in 2007 vs 32% in 2013). With regard to autologous reconstruction, microsurgical free flaps (mostly comprised of deep inferior epigastric artery perforator flaps) have supplanted latissimus flaps as the favored modality and comprised 13% to 14% of breast reconstruction cases overall from 2011 to 2013., Conclusion: In contrast to national trends, university-based plastic surgeons are performing a growing number of microsurgical free flaps as the preferred method for autologous breast reconstruction. Whereas implant-based reconstructions still predominate in academic practices, the trend of increasing preference toward implant-based reconstructions has slowed in recent years and revision reconstructions are on the rise.

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.

On August 8 2014, the World Health Organization (WHO) declared the outbreak of Ebola Virus Disease (EVD) evolving in West Africa since December 2013, a Public Health Emergency of International Concern (PHEIC). It is expected that the outbreak of Ebolavirus Disease (EVD) in West Africa will lead to increased testing of individuals in Europe for EVD. The severity of the situation in West Africa warranted a critical appraisal of the laboratory preparedness and response for EVD, with a focus on information needs for laboratories involved in diagnostics of rare viral diseases associated with the European Network for the Diagnostics of "Imported" Viral Diseases", ENIVD. Essential knowledge and knowledge gaps for an adequate laboratory response focusing on virus properties, infection kinetics, tests specifics and field performances were identified. An inventory of the laboratory capacity for EVD diagnostics among ENIVD laboratories was made.

Jun N-terminal kinase (JNK) often mediates apoptosis in response to cellular stress. However, during normal development, JNK signaling controls a variety of live cell behaviors, such as during dorsal closure in Drosophila embryos. During this process, the latent proapoptotic activity of JNK becomes apparent following Dpp signaling suppression, which leads to JNK-dependent transcriptional activation of the proapoptotic gene reaper. Dpp signaling also protects cells from JNK-dependent apoptosis caused by epithelial disruption. We find that repression of reaper transcription by Dpp is mediated by Schnurri. Moreover, reporter gene analysis shows that a transcriptional regulatory module comprising AP-1 and Schnurri binding sites located upstream of reaper integrate the activities of JNK and Dpp. This arrangement allows JNK to control a migratory behavior without triggering apoptosis. Dpp plays a dual role during dorsal closure. It cooperates with JNK in stimulating cell migration and also prevents JNK from inducing apoptosis.

In September 2013, dengue virus (DENV) infection was diagnosed in a German traveller returning from Japan. DENV-specific IgM and IgG and DENV NS1 antigen were detected in the patient’s blood, as were DENV serotype 2-specific antibodies. Public health authorities should be aware that autochthonous transmission of this emerging virus may occur in Japan. Our findings also highlight the importance of taking a full travel history, even from travellers not returning from tropical countries, to assess potential infection risks of patients.